HSP70: From molecular chaperone to integrative hub in castration-resistant prostate cancer therapeutic resistance

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Castration-resistant prostate cancer (CRPC) poses a significant therapeutic challenge, often driven by targets like androgen receptor splice variant 7 (AR-V7).
• Current treatment strategies face limitations due to complex resistance mechanisms.
• Heat shock protein 70 (HSP70) is increasingly recognized for its role in cellular stress response and protein homeostasis.

Purpose of the Study:

• To propose a conceptual framework viewing heat shock protein 70 (HSP70) as a central hub coordinating multiple resistance mechanisms in CRPC.
• To explore the hypothesis that HSP70 integrates pathways contributing to therapeutic resistance.
• To identify potential therapeutic strategies targeting HSP70 to overcome CRPC resistance.

Main Methods:

• Literature review and synthesis of existing evidence on HSP70 function in cancer.
• Analysis of HSP70's association with key resistance pathways, including AR/AR-V7 stabilization, lineage plasticity (PLXND1), ferroptosis modulation (MBOAT2), and synthetic vulnerability (HSP60).
• Conceptual modeling of HSP70 as an integrative resistance hub.

Main Results:

• HSP70 is implicated in stabilizing oncoproteins like AR and AR-V7, crucial drivers of CRPC.
• HSP70 may contribute to lineage plasticity via the Plexin D1 (PLXND1) pathway.
• HSP70 is linked to ferroptosis modulation through the MBOAT2 axis and exhibits synthetic vulnerability with HSP60.

Conclusions:

• HSP70 acts as a multidimensional hub coordinating diverse resistance mechanisms in CRPC.
• Targeting specific HSP70 interactions and functions represents a promising precision medicine approach.
• Leveraging HSP70 as a therapeutic target offers a framework to overcome CRPC resistance and improve patient outcomes.